title: Blood vessel tubulogenesis requires Rasip1 regulation of GTPase signaling.
abstract: Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular "tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. Mice lacking Rasip1 fail to form patent lumens in all blood vessels, including the early endocardial tube. Rasipl null angioblasts fail to properly localize the polarity determinant Par3 and display defective cell polarity, resulting in mislocalized junctional complexes and loss of adhesion to extracellular matrix (ECM). Similarly, depletion of either Rasip1 or Arhgap29 in cultured ECs blocks in vitro lumen formation, fundamentally alters the cytoskeleton, and reduces integrin-dependent adhesion to ECM. These defects result from increased RhoA/ROCK/myosin II activity and blockade of Cdc42 and Rac1 signaling. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sacharidou
authors.forename: Stephen
authors.initials: S
authors.lastname: Fu
authors.forename: Diana C
authors.initials: DC
authors.lastname: Chong
authors.forename: Brian
authors.initials: B
authors.lastname: Skaug
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: George E
authors.initials: GE
authors.lastname: Davis
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D016764:Cell Polarity; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism*; D011898:Ranidae; D015398:Signal Transduction; D015027:Zebrafish; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C541054:Rasip1 protein, mouse; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein